This work represents a 16-year collaboration between the Diabetes Branch and the Institute of Histology and Embryology at the University of Geneva. The initial observations demonstrated that polypeptide hormones are taken up by the cell through a process fo receptor-mediated endocytosis similar to other biologically important ligands that bind to cells. In the present study, using election microscopy, we find there is anatomical correlation between the dissocation of 125I-insulin and its localization on the cell surface. Three lines of work using electron microscopy have been followed: (a) We have continued to study the mechanism of receptor- mediated endocytosis. The insulin receptor is a tyrosine kinase, and early studies demonstrate that it is necessary to activate the kinase in order for a ligand to move from the microvillous to the nonvillous coated segment of the cell where it subsequently undergoes internalization; (b) We have continued the study of how ions such as calcium regulate the fusion of intracellular organelles such as endosomes; and (c) the newest studies have involved morphologic localization of newly synthesized receptor proteins from mutant cells and cells that have been mutated at specific glycosylation sites. In summary, all of these studies attempt to relate biochemical studies to specific morphologic correlates.